Hypercholesterolemia together with hypertension and smoking are known to be three major risk factors of ischemic heart disease. It is extremely important to control the cholesterol level in blood for prevention or treatment of coronary arteriosclerotic diseases as well as ischemic heart diseases.
With regard to medicaments to lower the cholesterol level in blood, attention has been paid to medicaments such as Cholestyramine, Colestipol and the like which capture bile acid and inhibit its absorption (disclosed, for example, in U.S. Pat. No. 4,027,009), medicaments such as Melinamide and the like which inhibit acyl coenzyme A cholesterol acyltransferase (ACAT) to inhibit absorption of cholesterol to intestine (disclosed in French Patent No. 1476596) and medicaments which inhibit biosynthesis of cholesterol.
As the inhibitor of biosynthesis of cholesterol, in particular, Lovastatin (disclosed in U.S. Pat. No. 4,231,938), Simvaststin (disclosed in U.S. Pat. No. 4,444,784), Pravastatin (disclosed in U.S. Pat. No. 4,346,227) and the like which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been used as the drug. However, when HMG-CoA reductase is inhibited, biosynthesis of not only cholesterol but also other components required for living bodies such as ubiquinone, dolichol, heme A and the like is inhibited. Then, there is a fear of side effects caused by the inhibition.
It is known that ubiquinone, dolichol, heme A and the like are synthesized from farnesyl pyrophosphate which is present in the pathway of cholesterol biosynthesis. Therefore, in order to prevent side effects caused by the loss of them, it is preferable to inhibit enzyme systems after farnesyl pyrophosphate in the pathway of cholesterol biosynthesis. Examples of such an enzyme includes squalene synthetase.
As squalene synthetase inhibitors, isoprenoid (phosphinylmethyl) phospbonate (Journal of Medicinal Chemistry, Vol. 31, No. 10, pp.1869 to 1871, 1988) and its derivatives (JP-A 1-213288, etc.) have been known. However, these compounds are not yet satisfactory in activities.